There is a strong comorbidity of narcolepsy and diabetes/obesity; however, the causal underlying mechanism is unclear. We recently performed studies using astrocyte-specific connexin 43 (Cx43) knockout mice (Cx43 KO) and found that they display both a narcolepsy-like phenotype and metabolic dysregulation. These linked phenotypes, arising from a single genetic manipulation, raise the potential that we have identified a cellular and molecular underpinning of this clinical linkage. We will use the collective strengths of Drs. Haydon and Kong, who are highly experienced in studying astrocytes and the control of sleep/wake cycles (Haydon) and the study of the hypothalamic neural circuits and metabolic control (Kong). Together, we will test the hypothesis that astrocytic connexins are essential for the supply of lactate as an energy substrate to orexinergic neurons, and in doing so, modulate orexinergic control of wakefulness and metabolic control. Pierre Magistretti and colleagues proposed an attractive hypothesis concerning metabolic coupling between astrocytes and neurons in which the astrocyte metabolizes glucose to lactate, then shuttle this energy source to neurons where lactate is converted to pyruvate, which is used in oxidative phosphorylation. This Astrocyte- Neuron Lactate Shuttle (ANLS) is attractive because: i) astrocytes contact the vasculature and express GLUT1, a glucose transporter, they can take up glucose. ii), astrocytes are considered to be biased towards glycolysis, and iii) neurons express monocarboxylate transporters (MCT) that are required for the uptake of lactate. We will extend our initial observations to test the hypothesis that astrocyte-derived lactate is required by orexinergic neurons to promote their electrical activity and that experimental manipulation of orexinergic neuronal activity is both necessary and sufficient to cause narcolepsy and metabolic disorders. Aim I: We will test the hypothesis that the deletion of Cx30 and Cx43 impairs the Astrocyte-Neuron Lactate Shuttle AND promotes narcolepsy and systemic metabolic dysfunction. Aim II: We will test the hypothesis that astrocyte-derived lactate modulates orexinergic neuron activity. Aim III: We will test the hypothesis that the activation of orexinergic neurons is sufficient to rescue normal phenotypes in connexin KO mice.